Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
Sci Adv. 2023 Aug 25;9(34):eadh5598. doi: 10.1126/sciadv.adh5598.
Members of the NSL histone acetyltransferase complex are involved in multiorgan developmental syndromes. While the NSL complex is known for its importance in early development, its role in fully differentiated cells remains enigmatic. Using a kidney-specific model, we discovered that deletion of NSL complex members KANSL2 or KANSL3 in postmitotic podocytes led to catastrophic kidney dysfunction. Systematic comparison of two primary differentiated cell types reveals the NSL complex as a master regulator of intraciliary transport genes in both dividing and nondividing cells. NSL complex ablation led to loss of cilia and impaired sonic hedgehog pathway in ciliated fibroblasts. By contrast, nonciliated podocytes responded with altered microtubule dynamics and obliterated podocyte functions. Finally, overexpression of wild-type but not a double zinc finger (ZF-ZF) domain mutant of KANSL2 rescued the transcriptional defects, revealing a critical function of this domain in NSL complex assembly and function. Thus, the NSL complex exhibits bifurcation of functions to enable diversity of specialized outcomes in differentiated cells.
NSL 组蛋白乙酰转移酶复合物的成员与多种器官发育综合征有关。虽然 NSL 复合物在早期发育中很重要，但它在完全分化的细胞中的作用仍然是个谜。我们使用肾脏特异性模型发现，有丝分裂后足细胞中 NSL 复合物成员 KANSL2 或 KANSL3 的缺失会导致灾难性的肾功能障碍。对两种主要分化细胞类型的系统比较表明，NSL 复合物是两种分裂和非分裂细胞内纤毛内运输基因的主要调节因子。NSL 复合物缺失导致纤毛丢失和纤毛成纤维细胞中 Sonic Hedgehog 信号通路受损。相比之下，非纤毛足细胞则表现出微管动力学的改变和足细胞功能的破坏。最后，野生型而非双锌指（ZF-ZF）结构域突变型 KANSL2 的过表达挽救了转录缺陷，揭示了该结构域在 NSL 复合物组装和功能中的关键作用。因此，NSL 复合物表现出功能的分叉，以使分化细胞中的特殊结果具有多样性。
